The present invention is concerned with a composition suitable for implantation at or in the vicinity of a body orifice or sphincter muscle to aid correct function.
Many body unctions rely upon the correct functioning of sphincter muscles. For example, the pyloric sphincter controls when the contents of the stomach pass into the small intestine. Similarly, the urethral sphincter controls when the contents of the bladder are voided. Incorrect functioning due to premature relaxation of such sphincter muscles can be problematic, and in the case of stress urinary incontinence (malfunction of the urethral sphincter) highly distressing to the patient.
Premature relaxation of a sphincter muscle often occurs when the Sphincter muscle itself lacks sufficient bulk to adequately close the orifice in question. One option to overcome the problem is by implanting bulking material in the submucosa surrounding the orifice, thereby reducing the area to be closed by the sphincter muscle. Generally, the bulking material is injected into the site to augment the soft tissue present. Suitable bulking materials are available commercially and are generally in the form of spherical particles or beads based on silicone, PTFE or collagen. These beads are suspended in a carrier fluid such as glycerine or hydrogel. The carrier fluid ants as a lubricant during the implantation process and assists expulsion of the implant from the syringe through an endoscopic needle. The carrier fluid is eliminated from the body and the implant material gradually becomes encapsulated by collagen at the implant site. The collagen capsule which forms around the implanted material adds to the bulk at the site. One such bulking material is MACROPLASTIQUE (Trade Mark) of Uroplasty, Inc.
Existing implants do not biodegrade but remain permanently in the body of the patient. Recently, concern has been raised that such implants may gradually migrate away form the site of implantation during the lifetime of the patient. Thus, the original problem may recur as the size of the implant gradually decreases due to migration of the beads inserted. The patient will therefore need to undergo a further procedure in order to insert more beads at the site concerned The migrating implant may, in addition, cause irritation and such implants have been reported to be associated with cancer, auto-immune and connective tissue disease.
In addition to stress urinary incontinence, such implants have also been used to prevent vesicoureteral reflux. Vesicoureteric reflux is a condition occurring in babies and small children where the ureteral orifice is incompletely closed during contraction of the bladder. Urine is thus allowed to reflux back up the ureter and can cause recurrent infections of the kidneys, frequently leading to permanent kidney damage. In a similar manner to stress urinary incontinence, it is possible to insert pellets or beads of silicone rubber or teflon in the submucosa of the bladder wall close to the ureteral orifice. Again, the procedure requires the permanent insertion of the implant.
Paediatric vesicoureteral reflux usually resolves itself as the bladder wall thickens. By the time a child is five years old the urinary system has usually matured sufficiently to make the implant material redundant. Again, it is possible for implant material to migrate from the implant site causing obstruction, occlusion or embolism at another site. Implants have also been associated with cancer, auto-immune and connective issue disease.
The present invention provides a composition suitable for implantation in soft tissue (for example at or around a body orifice) in order to augment the volume of soft tissue. The composition of the present invention comprises particles of biodegradable glass in a suitable carrier medium. The carrier medium is required to ensure easy injection at the site of interest.
The currently available silicone, PTFE and collagen beads are all deformable. This property aids injection of the beads, butalso contributes to their ability to migrate from the site of interest. By contrast, the glass particles of the present invention are non-deformable.
The composition is suitable for insertion in the bladder submucosa to treat stress urinary incontinence or vesioureteric reflux by bulking up the area around the urethral sphincter or urethral orifice respectively.
Optionally, the glass particles dissolve over a relatively long period, typically one to five years, more usually one to two years.
Preferably, the glass particles are irregularly shaped. This contrasts to the commercially available implants which are formed from spherically shaped beads. The irregular shape of the glass particles encourages their encapsulation in fibrous tissue. Such encapsulation further reduces the rate of dissolution of the glass and also helps to prevent migration of the particles.
Typically, the glass particles used in the present invention may have a diameter of from 50 xcexcm up to 2000 xcexcm. More conveniently, however, the average diameter of the particles will be 1000 xcexcm or less, usually 500 xcexcm or less. Good results have been obtained with particles having an average diameter of 300 to 200 xcexcm or less, for example 150 xcexcm or less.
Particles having smaller diameters, e.g. 100 xcexcm or less, particularly of approximately 50 xcexcm, or even less, are of especial interest.
One advantage of the present invention is that it is possible to form glass particles having such small diameters (e.g. 50-100 xcexcm). Where such small particles are used that problems associated with injection are reduced. Additionally, once the particles have been located in the site of interest, the outside surfaces of the particles becomes tacky as the particles begin to dissolve into body fluids so that the particles become associated in situ in a sticky cohesive mass.
Such particle association greatly reduces the rate of particle migration and the health risks associated therewith. No such association has been observed with the prior art silicone, PTFE or collagen beads.
A carrier medium is generally used to assist injection of the particles. The carrier medium is typically glycerol, but other conventional carrier mediums (e.g. corn oil, sesame oil, sunflower oil or olibas oil) may also be used. A surfactant and/or suspending agent may also be included in the composition. Typical surfactants include, for example, benzyl benzoate, ethyl oleate and benzyl alcohol. Typical suspending agents include, for example, carboxymethylcellulose and alginate.
In a further aspect the present invention provides a method of augmenting an area of soft tissue in a body (e.g. thickening a wall of a body organ), said method comprising injecting a composition into the soft tissue (e.g. the submucosa of said wall), said composition comprising particles of a biodegradable glass.
Thus, the present invention provides a method of combatting vesicoureteric reflux by injecting a composition of the present invention into the bladder submucosa close to the ureteral orifice such that urine is substantially unable to pass up the ureter upon contractor of the bladder.
Likewise, if the composition of the present invention is injected into the submucosa in the vicinity of the urethral sphincter, stress urinary incontinence may be overcome due to the xe2x80x9cbulkingxe2x80x9d effect of the injected particles.
The present invention may be used at other body areas where soft tissue augmentation has a beneficial effect. Examples include injection around the anal passage, in order to reduce blood flow at the site and hence combat development of haemorrhoids (piles). Likewise soft tissue augmentation may be beneficial to temporarily correct an xe2x80x9cincompetentxe2x80x9d cervix which would prevent sustainment of a pregnancy. The soft tissue augmentation of the present invention may further be used to build up portions of the body damaged by accident or surgery, allowing healing to take place. Particular mention may be made of reshaping the facial area of a patient. From the above examples it is clear that the composition of the present invention may be used not only to treat existing conditions but also for prophylactic and cosmetic purposes.
Generally the glass will be a controlled release glass (CRG). CRGs sare vitreous inorganic polymers which dissolve over a pre-programmed period leaving virtually no residue. The components of manufacture are all present as natural body constituents hence CRCs show little or no cytotoxicity and exhibit a minimal tissue reaction.
The use of glasses which can dissolve in water and body fluid are well-known. These glasses are formed from phosphorus pentoxide and may be modified to dissolve over a period of months or years, as required. To date, such glasses have been used, in medicine, for the controlled release of a number of agents, for example, drugs, hormones and trace elements.
It is know that certain glasses, in which the usual glass former, silicon dioxide, of traditional glasses is replaced with phosphorus pentoxide as the glass former, are soluble in water and body fluids. The rate of dissolution is controlled largely by the addition of glass modifiers such as calcium and magnesium oxide. In simple terms, the greater the concentration of the modifier the slower the rate of dissolution. The rates of dissolution which can be imparted to the glasses may range from minutes to months or even to several years. It is known to include in such compositions quantities of trace elements such as copper, cobalt and selenium which will released from the glass as it slowly dissolves over the selected period of time.
The use of water-soluble glasses has been described for a variety of purposes in the literature. For example, UK Patent Specifications Nos 1,565,906, 2,079,152, 2,077,585 and 2,146,531 describe the gradual dissolution of the glasses as providing a means of controlled release of drugs, hormones, fungicides, insecticides, spermicides and other agents with which the glasses have been impregnated. The glasses are used, for example, in the form of an implant or bolus.
UK Patent Specification No 2,030,559 describes the use of selenium impregnated water-soluble glass for providing controlled release of the selenium as a trace element into cattle and sheep, the glass being applied as a subcutaneous insert. UK Patent Specification No 2,037,735 also describes a subcutaneous implant of water-soluble glass, and in this case the glass is impregnated with copper; minor quantities of trace elements such as boron, arsenic, iodine, manganese, chromium, silver, gold and gallium may also be included.
Water-soluble glass has also been proposed for use in prosthetics, for example in UK Patent Specification No 2,099,702, and for use in anticorrosive paints, as described in UK Patent Specification No 2,062,612. Further the literature provides for the use of such glasses in the controlled release of ferrous and ferric ions into the human or animal body by ingestion or implantation of the glass (UK Patent Specification No 2,081,703), and for the use of glasses in the controlled release of ions such as lithium, sodium, potassium, caesium, rubidium, polyphosphate, calcium and aluminium to patients by inclusion of the glass in a drip feed line (UK Patent Specification No 2,057,420).
Optionally he water-soluble glass may be a silver containing water-soluble glass. Advantageously the silver content my be introduced into the glass composition in the form of silver orthophosphate.
Suitable glasses include, for example, the ARGLAES(trademark) glass of Giltech Limited.
The glass may be adapted by the use of glass modifiers to give a sustained release of silver ions over a set period.
In one embodiment the water-soluble glass comprises an alkali metal oxide M2O, an alkaline earth oxide MO, phosphorus pentoxide P2O5 and silver oxide (Ag2O) or silver orthophosphate (Ag3PO4).
Most preferably, said glass contains not more than 40 male % M2O or MO, not less than 10 mole % M2O or MO, and not more than 50 mole % nor less than 38 mole % phosphorus pentoxide, optionally with the inclusion of 0.05 to 5.0 mole % silver oxide or orthophosphate.
Said alkali metal oxide may be sodium oxide (Na2O), potassium (k2O) or a mixture thereof; and said alkaline earth oxide may be calcium oxide (CaO), magnesium oxide (MgO), zinc oxide (ZnO) or a mixture thereof.
The glass may also contain less than 5 mole % silicon dioxide (SiO2), boric oxide (B2O3), sulphate ion (SO42xe2x88x92), a halide ion, copper oxide (CuO) or a mixture thereof.
Typically the soluble glasses used in this invention comprise phosphorus pentoxide (P2O5) as the principal glass-former, together with any one or more glass-modifying non-toxic materials such as sodium oxide (Na2O), potassium oxide (K2O), magnesium oxide (MgO), zin oxide (ZnO) and calcium oxide (CaO). The rate at which the silver-release glass dissolves in fluids is determined by the glass composition, generally by the ratio of glass-modifier to glass-former and by the relative proportions of the glass-modifiers in the glass. By suitable adjustment of the glass composition, the dissolution rates in water at 38xc2x0 C. ranging from substantially zero to 25 mg/cm2/hour or more can be designed. However, the most desirable dissolution rate R of the glass is between 0.01 and 2.0 mg/cm2/hour. The water-soluble glass is preferably a phosphate glass, and the silver may advantageously be introduced during manufacture as silver orthophosphate (Ag3PO4). The content of silver and other constituents in the glass can vary in accordance with conditions of use and desired rates of release, the content of silver generally being up to 5 mole %. While we are following convention in describing the composition of the glass in terms of the mole % of oxides, of halides and of sulphate ions, this is not intended to imply that such chemical species are present in the glass nor that they are used for the batch for the preparation of the glass.
The glass may be formed by a number of methods. It may simply be cast by conventional or centrifugal procedures, or it may be prepared via one or more stages of rod, fibre or tube drawing. Other preparation techniques include foamed glass. Following glass formation it will be comminuted into finely divided form.
Optionally, the composition of the present invention may contain an active ingredient. The term xe2x80x9cactive ingredientxe2x80x9d is used herein to refer to any agent which affects the metabolism or any metabolic or cellular process of the patient (including growth factors and living cells), promotes healing, combats infection, hypergranulation or inflammation. Antibiotics and other anti-bacterial agents, steroids, painkillers etc are all suitable. Optionally, the active ingredient may be in delayed-release or controlled-release form.